S1P1 agonist 7 is a potent and orally active β-arrestin-biased S1P1 agonist [EC50 (G-protein) = 12.7 nM, EC50 (β-arrestin) = 3.23 nM], exhibiting strong immunomodulatory activity and favorable safety. It has excellent metabolic stability, shows weak to moderate CYP inhibition, and demonstrates high selectivity without affecting the S1P3 receptor. In a mouse model of experimental autoimmune encephalomyelitis, S1P1 agonist 7 shows favorable pharmacokinetic properties, effectively reduces circulating lymphocyte counts, and significantly alleviates disease severity. This compound is applicable for research in multiple sclerosis.

S1P1 agonist 7 (compound 28) demonstrates a β-arrestin bias 4.51 times greater than Fingolimod, with a G protein signaling pathway EC50 of 12.7 nM and a β-arrestin recruitment EC50 of 3.23 nM. This compound shows high stability in human, rat, and mouse liver microsomes at concentrations of 1-10 µM over 15-60 minutes and exhibits no significant inhibitory effect on most CYP enzymes at a 10 µM concentration. In Chem-4/G15 and CHO-K1 EDG1 cell models, starting from a concentration of 100 μM and gradient diluted for 90 minutes, S1P1 agonist 7 displays high selectivity for the S1P1 receptor, with G protein signaling pathway EC50 value of 0.014 μM and β-arrestin recruitment EC50 value of 0.0023 μM, and only weak activity on S1P5 receptor. Additionally, S1P1 agonist 7 (0.041-10 μM for 2 minutes) causes no observable changes in peak frequency or beating rate in human iPSC-derived cardiomyocytes, even at the highest tested concentration.

S1P1 agonist 7, administered orally at doses of 1, 3, and 10 mg/kg, reduces peripheral blood lymphocyte counts in C57BL/6N mice. Additionally, daily oral administration of S1P1 agonist 7 at 10 mg/kg for 23 consecutive days demonstrates significant protective effects in the MOG 35-55-induced EAE mouse model, slowing disease onset, inhibiting progression, and mitigating related pathological damage.